tbuckley/cabot-search huggingface dataset:
Abstract 1561: Preclinical examination of PLK1 inhibitors for the treatment of diffuse midline gliomas
Authors: Elisha Hayden, Laura Franshaw, Dannielle Upton, Jie Liu, Hieu Nguyen, Swapna Joshi, Maria Tsoli, Emmy Dolman, Benjamin Rayner, David Ziegler
Journal: Cancer Research (2023)

Abstract Diffuse Midline Gliomas (DMGs) are devastating and incurable pediatric brain tumours. DMGs are characterised by epigenetic aberrations in the form of histone modifications, coupled with mitotic abnormalities, which together drive a stem-like transcriptional cell state that is critically dependent on the cell cycle. Polo-like kinase 1 (PLK1) is a pivotal regulator of mitosis and cell cycle progression. To determine an effective therapeutic strategy against DMG, we characterised the anti-tumour potential of PLK1 inhibition, either alone or in combination with radiotherapy. We show that targeting PLK1 with small molecule inhibitors BI2536 and BI6727 (volasertib) reduced DMG colony formation and cell proliferation, and induced G2/M checkpoint arrest and apoptosis in vitro at physiologically achievable, clinically relevant concentrations. When combined with radiotherapy, PLK1 inhibitors acted as potent radiosensitisers with synergistic suppression of DMG survival. We further show that PLK1 inhibitors exert potent anti-tumour effects in highly aggressive orthotopic DMG models, effectively extending the median survival of tumour harbouring mice both as a single agent and enhanced in combination with radiotherapy. We further demonstrate a potential novel role for PLK1 in defining an oncogenic transcriptional state in DMG by acting as a conduit between cell cycle progression and the DMG epigenome through modulation of polycomb repressive complex 2 (PRC2) activity and its resultant histone methyltransferase function. Together, these data indicate that targeting PLK1 is a highly promising therapeutic strategy to arrest DMG tumorgenicity. This data has formed the basis for a planned international Phase 1/2 trial of the PLK1 inhibitor volasertib in combination with radiotherapy in paediatric patients with DMG. Citation Format: Elisha Hayden, Laura Franshaw, Dannielle Upton, Jie Liu, Hieu Nguyen, Swapna Joshi, Maria Tsoli, Emmy Dolman, Benjamin Rayner, David Ziegler. Preclinical examination of PLK1 inhibitors for the treatment of diffuse midline gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1561.
Abstract 2875: Evidence of immunosuppression in patients with breast ductal carcinoma in situ
Authors: Sedigheh Taghinezhad-S, Amir Hossein Mohseni, Pamela L. Beatty, Leisha A. Emens, Olivera J. Finn
Journal: Cancer Research (2023)

Abstract Introduction: Ductal carcinoma in situ (DCIS) is a noninvasive precursor to invasive breast cancer. Although not all DCISlesions progress to cancer, most DCIS are treated as early breast cancer, given the uncertainty of which lesions will progress. The current increase in the incidence of DCIS has sparked interest in the immune contexture of the DCIS lesions as well as the immune status of DCIS patients, as a means to predict which DCIS lesions will progress to cancer. Studies done so far in invasive breast cancer showed that the immune system can mediate both tumor-promoting influence (via T regulatory (Treg) cells, M2 macrophages, myeloid-derived suppressor cells (MDSCs)), as well as tumor-suppressing influences (via CD8+ and CD4+ effector T cells, natural killer cells (NK), M1 macrophages, tissue-resident memory T (Trm) cells, B cell and dendritic (DCs) cells). Similar studies are still lacking in DCIS. Our aim was to start closing the gap in our understanding of the DCIS immune microenvironment, which will pave the way for novel preventative and therapeutic strategy. Methods: We analyzed by flow cytometry peripheral blood mononuclear cells (PBMCs) from newly diagnosed DCIS patients for the presence of various immune cell types expressing specific phenotypic markers of immune effectors or immune suppressors and compared them with PBMC from age-matched healthy individuals. Results: We found a statistically significant increase in the frequency of FoxP3+ regulatory T cells in DCIS PBMC compared with healthy controls. There was also a significant increase in Tim-3+CD8+ T effector memory cells (P= 0.035) and Tim-3+ CD8+ NKT cells (P = 0.033) in the PBMCs of patients with DCIS compared with healthy controls. T cells expressing other exhaustion markers, such as PD-1+ and LAG-3+ were present at very low levels in both groups. Conclusion: Our results suggest that some of the many immunosuppressive mechanisms seen in patients with invasive breast cancer, such as regulatory T cells, are already present in pre-cancer DCIS. Evidence of the beginning of immune suppression is also reflected in the increased frequency of CD4+ and CD8+ T cells expressing the exhaustion marker Tim-3. Citation Format: Sedigheh Taghinezhad-S, Amir Hossein Mohseni, Pamela L. Beatty, Leisha A. Emens, Olivera J. Finn. Evidence of immunosuppression in patients with breast ductal carcinoma in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2875.
Abstract 4649: Design and validation of ultrahigh-plex discovery panels for immuno-oncology and oncology
Authors: Yan He, Shannon Berry, Olive Shang, Michael McLane, Nicholas Ihley, Yi Zheng
Journal: Cancer Research (2023)

Abstract Introduction Ultrahigh-plex single-cell spatial phenotyping is revolutionizing cancer research through deeper interrogation of cellular and protein-level co-expression, localization, and arrangements within cancer tissues. To enable in-depth characterization of the tumor microenvironment (TME), we have developed and validated pre-optimized antibody panels on cancer tissues to reveal key cell types and cellular architecture using the PhenoCycler™-Fusion system. Here, we present our methodology for the development and validation of multiplex spatial phenotyping panels for oncology and immuno-oncology. Methods We designed panel modules such that each module answers specific biological questions about the TME and can be multiplexed together for a more comprehensive view of the structure and function of the tumor and TME. The resulting PhenoCode™ Discovery panel modules include markers that identify key immune cell types, immune activations and checkpoints, mediators of proliferation, and other hallmarks of cancer. Each antibody in the panel module was conjugated to an oligo barcode and stained on human formalin-fixed paraffin-embedded (FFPE) tissue. The slide was imaged on a PhenoCycler™-Fusion platform, where dye-labeled oligo reporters (complementary to the barcodes) are hybridized to the barcode to visualize the antibody. The results were compared serial sections run with a 3,3’-Diaminobenzidine (DAB) chromogenic immunohistochemistry assay to ensure specificity of the antibody was retained. Antibody concentration, exposure time, and corresponding dye were further optimized, verified, and validated as a whole module using tonsil and cancer tissues based on image analysis and intensity analysis, to achieve an ultrahigh-plex detection. Results and Conclusions In this study, we showcased the rigorous process used for development and validation of PhenoCode™ Discovery panel modules and demonstrated how they can seamlessly work together to collect more data out of one tissue sample. The introduction of these pre-optimized antibody panel modules mark a pivotal point in the evolution of ultrahigh-plex spatial phenotyping. They not only simplify experimental design and assay set up, with panels that make it easier for researchers to answer important questions with this technology, but also save precious time and resources, while reducing overall costs. Citation Format: Yan He, Shannon Berry, Olive Shang, Michael McLane, Nicholas Ihley, Yi Zheng. Design and validation of ultrahigh-plex discovery panels for immuno-oncology and oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4649.
Abstract 1092: Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC)
Authors: Minal Nenwani, Abhinav Achreja, Olamide Animasahun, Itisam Sarangi, Jyotirmoy Roy, Srinadh Choppara, Fulei Wuchu, Miya Paserba, Anjali Mittal, Sergio Quispe, Aradhana Mohan, Meredith Morgan, Theodore S. Lawrence, Deepak Nagrath
Journal: Cancer Research (2023)

Abstract One of the most challenging aspects of PDAC is intense therapeutic resistance towards radiotherapy. Cellular signaling pathways are tightly regulated to protect and withstand constant DNA-damaging insults. Similarly, pancreatic cancer cells are known to activate important metabolic events in the advent of cellular stress. Fuel sources obtained via the high metabolic flexibility of PDAC cells confer on them enhanced survival and the ability to escape therapy-induced cell death. To this end, we aim to dissect the role of altered metabolic reprogramming in radioresistant PDAC cells. Investigation of systemic metabolic changes post-radiation of 8Gy in in vitro systems revealed reduced total NAD/NADH ratio and hinted at the increased dependency of PDAC cells on the one-carbon metabolic pathway. Using combinatorial stable-isotope tracing techniques, we confirmed the role of methylene tetrahydrofolate dehydrogenase (MTHFD1/2) enzymes as key regulators in maintaining total NAD/NADH ratio in irradiated cells. Moreover, inhibition of the one-carbon metabolic pathway hindered the ability of PDAC cells to resolve radiation-induced DNA damage. In summary, we propose that PDAC cells modulate the flux of MTHFD1/2 enzymes to reprogram their metabolic state and generate intermediates for DNA repair and cell survival, thus establishing MTHFD1/2 enzymes as potential therapeutic targets to tackle radioresistance. Citation Format: Minal Nenwani, Abhinav Achreja, Olamide Animasahun, Itisam Sarangi, Jyotirmoy Roy, Srinadh Choppara, Fulei Wuchu, Miya Paserba, Anjali Mittal, Sergio Quispe, Aradhana Mohan, Meredith Morgan, Theodore S. Lawrence, Deepak Nagrath. Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1092.
Abstract 1965: Racially divergent mitochondrial ND5 gene mutation promotes prostate cancer progression and confers therapeutic resistance
Authors: Kunwar Somesh Vikramdeo, Christopher E. Keel, Martin J. Heslin, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta
Journal: Cancer Research (2023)

Abstract Compared to European American (EA), African American (AA) men often develop lethal forms of prostate cancer (PCa) and experience high mortality despite having a primary diagnosis of low-risk indolent disease. Understanding the molecular basis of this disparity is thus a dire need for better prevention, accurate monitoring, and guided therapeutics. Aggressive cancer growth is intimately associated with the reprogramming of metabolism and apoptosis, where mitochondrial DNA (mtDNA) alterations play a critical role. In the mitochondrial energy generation cascade, respiratory complex I (RCI) serves as the entry gate to initiate electron transfer through the oxidative phosphorylation system (OXPHOS). Alteration in RCI function could alter metabolism and attenuate apoptosis, hallmarks of malignant progression. Through next-generation sequencing of the entire mitochondrial genome, we identified a prevalence of RCI gene mutations in the AAPCa compared to the EAPCa patients. Among the RCI mutations, a homoplasmic 13709C&amp;gt;G mutation in NADH dehydrogenase 5 (ND5) was identified as the most frequently occurring mtDNA mutation among AA men. Forced expression of the 13709C&amp;gt;G mutation in the mitochondria of the AA-PCa patient-derived MDA PCa 2b and EA-PCa patient-derived LNCaP cells, remarkably enhanced their growth and malignant potential. The increased tumorigenicity was associated with a significant increase in the production of mitochondrial reactive oxygen species (ROS), O2 consumption, overall respiration, and ATP production. The ND5-mutant PCa cells exhibited remarkable resistance to androgen deprivation and docetaxel treatment. Induction of CXCR4, HIF-1α, and NF-kB was also noted in these ND5-mutant PCa cells. In clinical tissue samples, an abundance of CXCR4 protein expression was evident in AA-PCa patients harboring ND5 gene mutation but not in the AA or EA-PCa patients with wild-type ND5. Blockade of CXCR4 expression in the ND5-mutant PCa cells diminished NF-kB activity, thereby suggesting a potential role of the CXCR4/HIF-1α/NF-kB signaling axis in ND5 mutation-driven PCa tumorigenesis. The RCI-ND5 could be an attractive target for therapeutic and biomarker development for the better management of PCa in racially disparate populations. Citation Format: Kunwar Somesh Vikramdeo, Christopher E. Keel, Martin J. Heslin, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta. Racially divergent mitochondrial ND5 gene mutation promotes prostate cancer progression and confers therapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1965.
Abstract 3138: Topological analysis of spatial transcriptomics reveals different spatial interaction patterns in tumor microenvironment of lung cancer
Authors: Sungwoo Bae, Hyekyoung Lee, Kwon Joong Na, Dong Soo Lee, Hongyoon Choi, Young Tae Kim
Journal: Cancer Research (2023)

Abstract Background: As the tumor microenvironment (TME) consists of various cell types with complex spatial interaction, its spatial organization patterns affect response to immune-oncology treatment. Therefore, describing the spatial composition and interaction of cells in the tumor microenvironment (TME) is necessary. Here, we developed a tool, STopover, which adopts topological analysis in spatial transcriptomics to reveal cell-cell colocalization patterns in TME and capture the key components and niche of intercellular communication, and applied it to human lung cancer data. Methods: The spatial colocalization pattern of pairs of features was defined using topological data analysis with Morse filtration. The spatial network of spatial gene expression data was generated for each sample and then the patterns were summarized as connected components (CCs) based on the spatial distance between unit tissue regions and the persistence of each CC. The global and local extent of spatial overlap of a feature pair was calculated as Jaccard indices between extracted CC pairs. We applied STopover to 11 barcode-based spatial transcriptomic data of human lung adenocarcinoma with different PD-L1 expressions. Spatial mapping of cell types in TME was performed by CellDART. In addition, image-based spatial transcriptomic data of lung cancer were also used to find key spatial molecular interactions in TME using STopover. Results: First, STopover disclosed the distinct immune and stromal infiltration patterns in lung cancer tissues. Spatial colocalization of cancer cells and T-cells was heterogeneous and correlated with the immune-related markers such as MHC class I signature. The cancer types were clustered according to spatial colocalization patterns of various immune cells with cancer cells, which showed different infiltration patterns of immune cells. Moreover, STopover could estimate the top cell-cell interaction and emphasize the key locations based on the literature-supported ligand-receptor database. Conclusion: STopover is expected to account for significant spatial cell interactions in tumor-immune and tumor-stromal components and could be utilized as a platform to decipher the mechanisms underlying immune-oncology treatment response. Citation Format: Sungwoo Bae, Hyekyoung Lee, Kwon Joong Na, Dong Soo Lee, Hongyoon Choi, Young Tae Kim. Topological analysis of spatial transcriptomics reveals different spatial interaction patterns in tumor microenvironment of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3138.
Abstract 4372: Hierarchy of prognostic quality markers after curative-intent resection of stage IA non-small cell lung cancer
Authors: Huibo Shao, Yu-Sheng Lee, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Meredith A. Ray, Matthew Smeltzer, Raymond U. Osarogiagbon
Journal: Cancer Research (2023)

Abstract Introduction. 5-year disease-free survival after curative-intent resection of stage IA NSCLC approximates 65%. The quality of resection and differences in cancer biology probably account for most curative-intent treatment failure. We evaluated the hazard associated with markers of surgical quality. Methods. Using the population-based Mid-South Quality of Surgical Resection cohort, we compared outcomes of pathologic IA NSCLC resections from 2009 to 2021. With the stringent International Association for the Study of Lung Cancer complete (R0) resection for reference, we evaluated eight quality benchmarks: wedge resection; resections with positive margins; non-examination of lymph nodes (LN) from anywhere (pNX), mediastinal (pNXmed), intrapulmonary, hilar, low paratracheal and subcarinal stations. We evaluated hazard ratios (HR), adjusted for age, sex, insurance, histology, comorbidity, preoperative staging and technique of resection (95% CI) from Proportional Hazards models. Results. Of 2,243 resections, 906 (41%) were R0; 1,333 were non-R0, including 3% R1/R2, 13% pNX, 15% wedge resections, 15% pNXmed, 45% without subcarinal, 41% without hilar, 47% without low paratracheal, and 36% without intrapulmonary LNs.Compared to IASLC-R0, adjusted HRs were: 2.04 (1.21-3.44) for R1/R2; 1.75 (1.33-2.31) for pNX; 1.64 (1.26-2.14) for wedge resections; 1.35 (1.12-1.63) for non-examination of intrapulmonary LN; 1.33 (1.03-1.72), pNXmed; 1.25 (1.02-1.53), non-examination of hilar LN; 1.15 (0.95 - 1.39) missing station 4; and 1.11 (0.90-1.37) missing station 7 LNs. Conclusion. Surgical quality, indicated by markers of LN evaluation, have significant impact on long-term survival and should be required selection criteria or stratification factors in lung cancer surgery trials. Citation Format: Huibo Shao, Yu-Sheng Lee, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Meredith A. Ray, Matthew Smeltzer, Raymond U. Osarogiagbon. Hierarchy of prognostic quality markers after curative-intent resection of stage IA non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4372.
Abstract 6656: Expression pattern and clinicopathological implication of B7 family immune checkpoints, VTCN1 and HHLA2, in non-small cell lung cancer
Authors: Sojung Lim, Jaemoon Koh, Seung Geun Song, Jeemin Yim, Bogyeong Han, Young A Kim, Doo Hyun Chung, Yoon Kyung Jeon
Journal: Cancer Research (2023)

Abstract Background: Efforts are needed to discover novel immunotherapeutic targets in non-responders of current immunotherapies. VTCN1 (B7-H4/B7x/B7S1) and HHLA2 (B7-H7/B7y) are B7 family co-inhibitory molecules reported to be expressed in PD-L1-negative or EGFR-mutant lung adenocarcinoma (LUAD). To elucidate the clinicopathological implications of these two immune checkpoints, we checked their detailed expression patterns including intratumoral heterogeneity. Methods: VTCN1 and HHLA2 expression were evaluated in public single-cell RNA sequencing (scRNAseq) and The Cancer Genome Atlas (TCGA) dataset. Their immunohistochemistry (IHC) was performed on tissue microarrays of 413 LUAD and 382 lung squamous cell carcinoma (LUSC) specimens. Intratumoral heterogeneity was evaluated by IHC on representative sections of 59 surgically resected LUAD and 49 LUSC specimens. Results: In LUAD scRNAseq, VTCN1 and HHLA2 were predominantly expressed on epithelial cells and were not co-expressed with PD-L1. However, IHC showed their expression in both tumor and immune cells. In TCGA analysis, there was a negative correlation between VTCN1 and PD-L1 (LUAD, r = -0.094, p = 0.033; LUSC, r = -0.227, p &amp;lt;0.001). VTCN1 and HHLA2 showed positive correlations in both TCGA (LUAD, r = 0.211, p &amp;lt;0.001; LUSC, r = 0.182, p &amp;lt;0.001) and IHC analysis (LUAD, p &amp;lt;0.001; LUSC, p = 0.016). They were more frequently expressed in EGFR-mutant LUAD (52.9% vs. 40.3%, p = 0.015 for VTCN1 in EGFR-mutant vs. wildtype; 59.8% vs. 40.5%, p &amp;lt;0.001 for HHLA2). CD8+ T-cell infiltration was significantly higher in VTCN1- or HHLA2-positive EGFR-mutant LUAD, but there was no significant relationship in EGFR-wildtype. In 60% of cases expressing both VTCN1 and HHLA2, the two showed spatially concordant expression (15 out of 24 LUAD; 3 out of 6 LUSC). However, VTCN1 and PD-L1 showed concordant expression in 37.2% of cases expressing both (6 out of 16 LUAD; 10 out of 27 LUSC). HHLA2 expression was associated with better overall survival in LUSC, but there was no significant difference in survival according to VTCN1 expression. Conclusions: VTCN1 and HHLA2 are frequently co-expressed in PD-L1-negative NSCLC, especially EGFR-mutant LUAD rich in CD8+ T-cells and can serve as potential novel immunotherapeutic targets. Citation Format: Sojung Lim, Jaemoon Koh, Seung Geun Song, Jeemin Yim, Bogyeong Han, Young A Kim, Doo Hyun Chung, Yoon Kyung Jeon. Expression pattern and clinicopathological implication of B7 family immune checkpoints, VTCN1 and HHLA2, in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6656.